DON'TPEEK!!

2013
GENETIC
DISORDERS
REVIEW r Part 1
Barbara
D. Bosch,M.D.

-';-

't,re g4y'1sa
lf t.s2tativ< J
---t-----'-------2013 GeneticDisordersReview- Part 1; BarbaraD. Bosch,l\,i.D. page2

Referencesfor USMLEStep 1-formatquestions (withmodifications):

4rhed. McGrawHillMedical,2003.
CatalanoE. Appleton& LanqeReviewof GeneralPatholoqv,
FendersonBA, StrayerDS, RubinR, RubinE. lllustrated
Q&A Reviewof Rubin'sPatholoqv,
2"d
ed. Lippincott
Williams
& Wilkins,2011.
GoldbergJ. LanqePracticeTestsUSMLEStep 1, 2nded. McGrawHillMedical,2006.
12rhed. McGrawHillMedical,2007.
KetteringJD, FletcherHM. PreTestMicrobioloqv,
2008.
KingMW. LanqeQ&AUSMLEStep1,6'ned. McGrawHillMedical,
KlattEC, KumarV- Robbinsand CotranReviewof Patholoqv,
3'ded. SaundersElsevier,2010.
KleinRM, EndersGC. PreTestAnatomv.Histoloov& Cell Bioloqv,3'ded. McGrawHillMedical,2007.
Le TT, KleinJ, ShivaramA. FirstAid Q&Afor the USMLEStep 1. McGrawHillMedical,2007.
Le T, KrauseK, KleinJ, ShivaramA. FirstAid Casesfor the USMLEStep 1. McGrawHillMedical,
2006.
MufsonM. PreTestPathophvsioloqv,
3'ded. McGrawHillMedical,2005.
PreTestClinicalViqnettesfor the USMLEStep 1. 4thed. McGrawHillMedical,2008.

A 36 year-oldwomangivesbirthat 34 weeks'gestationto a maleinfantwho livesfor onlyan hourafier

for heightand weight. Anomalies
delivery.On physicalexamination,
the infantis at the 30'npercentile

polydactyly,
includemicrocephaly,
a cleftlipandpalate,andpostaxial
withsixdigitson eachhandandfoot. Whichof thefollowing
karyotypes
ls mostlikelyto be presentin thisinfant?
A. 45,X
B. 46,XY
c. 47,XXY
D. 47,XY,43e'
E. 47,XY,+18
F. 69,XXY

2013 GeneticDisordersReview- Part 1; BarbaraD. Bosch,M.D. page3

Patausyndrome(trisomy13;47,XX,+13
or 47,XY,+13)
- f7 *.\t.
o riskincreases
withEglemalage

5 ro-\L

'-f'""A"'!lo^

- -'Jh*' J,lt'L

usuallycausedby meioticnondisjunction

clinicalfindingsincludeseverementalretardation,
cleftlip &/orpalate,

proboscis,
microcephaly,
structural
eJedgeeg and polydactyly
oftenassociated
with cardiacand renalanomalies,
as well as
holoprosencephaly
and rocker-bottom
feet
very poorprognosisdue to severemalformations

A 4 month-oldmaleinfantis witnessedhavinga seizureand is broughtto the emergencyroom. His mother

indicatesthat he has beenlistlessfor the pastfew daysand has alsovomiteda few times. The infanthasa
protuberant
abdomenwith hepatomegaly,
as well as thinextremities.Bloodwork revealsthat the infantis
hypoglycemic.In addition,his bloodpH is slightlyacidicwitha reducedlevelof bicarbonate.Blood
chemistryfurtherrevealselevatedtriglycerides.
Whichof the followingdisordersis mostlikelyin this
oatient?
A. Hurlersyndrome
B. McArdlesyndrome
C. Pomoedisease
D. Tay-Sachsdisease
E. von GierkediseaseLA liverbiopsyon this patientwill mostlikelyrevealdecreasedactivityof whichof the followingenzymes?
A. acid maltase
g
B. glucose-G-phosphatase
C. glycogensynthase
D. hexosaminidase
A
E. pyruvatekinase

2013ceneticDisorders
Review-part 1;BarbaraD. Bosch,M.D. page4

Von Gierkedisease(autosomalrecessive)
.

type I q!99gCtSlaGgC.dlSCeS.e
due to a deficiencyof gtucose-6-phosphatase

clinicalfindingsincludehepatomegaly
due to excessiveglycogen,shortstatureand poorgrowth

Iaboratorystudiesshow severefasting hypoglycemia(whichcan causefeaturessuch as

irritability,
seizures,apathy,hypotonia,
and evencoma),lacticacidemia, hyperlipidemia,
and

-+ d"*l s.lon.r
hyperurlqemia
o

definitivediagnosismadeby enzymeanalysis

W?

"n

//* *
,2vaC,../q.

A 27 year-oldman comesto the physicianfor an infertility

work-up.He and his wife havebeentryingto
conceivea childfor 6 years. On physicalexamination,
the patientis notedto be tall (6 ft., 5 in.). He also
exhibitsbilateralgynecomastia
and reducedtesticularslze. A semenanalysisrevealsoligospermia.
Laboratory
studiesdemonstrate
increasedserumlevelsof follicle-stimulating
hormoneand slightly
decreasedlevelsof testosterone.Whatis the mostcommoncauseof this patient'schromosomal
abnormality?
A. expansionof a trinucleotide
repeat
B. isochromosomeformation
t'
C. meioticnondisjunction
D. nonreciprocal
translocation
E. ringchromosome
formation
Whichof the followingkaryotypesis mostlikelyto be presentin this man?

A. 46,X,i(Xq) - f,,,e.-,
B. 46,XYdel(22q111" 0tgnyt

c. 47,XXY<
D. 47,XYY
- hko^nJk' t"'g, l"{
E. 48,XXYY
-gyry

/1,xxyy a^ a[ro o** l, G"l y*7

"-=.

2013 GeneticDisordersReview- Part'1;BarbaraD. Bosch,lVl.D. page 5

Klinefeltersyndrome
. most commonkaryotype: 47,XXY
.

usuallycausedby meioticnondisjunction

frequentcauseof malehypogonadism

clinicalfindingsincludean elongatedbodywitha eunuchoid

Fi

i{

bI

ti

l r

ia

sF

i;

rt

xt

? /

l,

: !

t ,

r!

*t

t l

rta

lt

: 3
:l:

st
ra

::

habitus,femaledistribution
of hair,high-pitched
voice,
A ,l LJ(

ca+tt{ . ,

TiA'r
-rt J r"tt )t"tYLl
.

J
br@

gynecomastia,and testicularatrophywith infertilitydue

Frontrl
baldnc:s

toolisosoermia

characterized
bv low serumlevelsof testosterone
and elevated
serumlevelsof follicle-stimulating
hormone(FSH),luteinizing

andestradiol
aL n4ffione (LH)

ihlinl

lettr|c|].t l.
Srov L\!er
chrll hri$
dcre!;pn:elt
F{xn1e.t}'lx
p!bi.lnjr

Snlxll
tc!ticulnt
sire

6(h,
A 25 year-oldwomancomesto the physiciancomplaining
of frequentnosebleeds,
recurrentbonepain
and increasingabdominalgirth. Physicalexamination
revealsmarkedhepatosplenomegaly.
A complete
bloodcountshowspancytopenia.Radiologic
studiesdemonstrate
severalradiolucent
bonedefects.A
bonemarrowbiopsyrevealsenlargedcellscontaininga finefibrillarymaterialreminiscent
of crumpled
tissuepaper. This patientmostlikelycarriesmutationsin the genethat encodeswhichof the following
types of hydrolyticenzymes?
f,
A. acid B-glucosidase
B. acid maltase

^1,"*[$l ebseA*"'L*

C. galactosidase
D. glucose-6-phosphatase
E. hexosaminidase
A
F. neuraminidase
G. sphingomyelinase

E|r

2013GeneticDisordersReview- Part '1;BarbaraD. Bosch,M.D. page6

Gaucherdisease(autosomalrecessive)
. * mostcommonlysosomalstoragedisorder
glucocerebrosides
(primarilyin the macrophage
/ mononuclear
phagocytesystem)
withfibrillary"crumpled
characterized
by markedlyenlargedmacrophages
tissuepaper"cytoplasm(Gauchercells),especiallyprominentin the:
-

+ pancytopenia
spleend markedsplenomegaly
and skeletalfractures
bonemarrow+ bonepain,deformities

and lymphadenopathy
liverand lymphoidtissue+ hepatomegaly

threevariants:
* type | - mostfrequentand mildestvariant(especially
prevalentin Jewsof
Europeandescent);presentsin adulthoodwithfeaturesas described
above;relativelynormallifespan
type ll - rareand mostseverevariant;presentsin infancywithfeaturesas
+ neuronal
cerebralinvolvement
describedabovePLUSperivascular
degeneration;
leadsto deathin infancyor earlychildhood
shortened
type lll - intermediate
variant;typicallypresentsin adolescence;
lifesDan
diagnosismadeby measurement
of enzymeactivity

is seenby a geneticcounselor.The
A 25 year-oldmanwith a historyof autismand mentalretardation
His maternaluncleis
man is notedto havean elongatedface,protrudingearsand macroorchidism.
similarlyaffected.What is the mostlikelyunderlyingcauseof this patient'sgeneticdisorder?
A. chromosomal
nondisjunction
B. chromosomeinversion
C. expansionof trinucleotide
repeatkD. frameshiftmutation
E. missensemutation
F. mitochondrial
DNA mutation
G. nonreciprocal
translocation

6Ze< 18,
2013GeneticDisorders
Review-Part1;BarbaraD. Bosch,l\4.D. pageT

mostfrequentlydue to a tripletnucleotiderepeatexpansion(nucleotide
sequence
CGG usuallyrepeatinghundredsto thousandsof times)withinthe FMRTgene
on the X chromosome;
femaleshravea highprobability
of amplification
of these
repeatsduringoogenesis
clinicalfindingsincludementalretardation
in affectedmalesand abouta thirdof
femalecarriers;autisticlike
behavior;attentiondeficitdisorders;an elongated
jaw and forehead;large,protruding
facewitha prominent
ears;and
(adultmales)
macroorchidism
diagnosedby DNAtesting

A 4 year-oldboy is admittedto the hospitalwith pneumoniaand respiratory

distress.The nursesreport
that the child'sbowelmovementsare greasyand havea pungentodor. A sweatchloridetest is positive.
Whichof the followingmechanisms
of diseaseis the mostlikelycauseof steatorrhea
in this child?
A. abnormaldietaryintake
B. bacterialovergrowth
C. hyperbilirubinemia
D. lack of pancreaticenzymesecretion 4a
E. obstruction
causedby meconiumileus
F. vitaminK deficiency
The abovepatientcarriesmutationsin the genethat encodeswhichof the followingtypesof protein?
A. membraneion channel
B. mitochondrial
transportprotein
C. Na'/K* ATPase
D. nucleartransportprotein
E. receptortyrosinekinase

2013GeneticDisordersReview- Part 1; BarbaraD. Bosch,l\,,|.D.pageB

Cystic tibrosis (autosomalrecessive)

.

mostcommonlethalgeneticdisorderin Caucasians

characterized
by a defectivechloridechannelprotein,
cysticfibrosistransmembrane
conductance
regulator

(cFrR)
.

CFIR gene is on chromosome

7; mostcommonmutation
producesa lossof phenylalanine
at position508
(4F508) of the protein
abnormalchloridechannelproteinleadsto thick
viscousmucus(whichobstructsthe ductsof
a varietyof organs)and decreasedreabsorption
of chloridein the eccrinesweatducts(which
resultsin elevatedsweatchloridelevels)
mostfrequentlyaffectedorgansincludethe lungs
(e.9.,recurrentinfectionswith Pseudornonas
aeruginosaand Staphylococcusaureus,chronic
bronchitis,
pancreas(ductal
bronchiectasis),
obstruction
leadingto pancreaticatrophyand
fibrosiswith resultantfat malabsorption),
salivaryglands,and the malereproductive
system(obstruction
or absenceof the vas
deferensresultingin infertility)
presentas meconiumileusin the
can occasionally
newborn
uncommoncomplication
is biliarycirrhosisdue to
. bileduct obstruction
diagnosismadeby elevatedsweatchloridelevels
DNAanalysis;now routinenewbornscreening
mostcommoncauseof deathis oulmonarvdisease

2013 GeneticDisordersReview- Part 1;BarbaraD. Bosch,lvl.D. page9

A 9 month-oldgirlwho was bornat 39 weeks'gestationis broughtto the physicianbecauseof motor

retardation.Her motherstatesthat she couldsit up at 5 months,but she can no longerdo so. Six
monthslater,the girl becomesunresponsive
to visualor auditorystimuli.Fundoscopic
examination
showsperipheralpallorwith accentuation
of the reddishcolorareain the maculaof botheyes. Whichof
the followinggeneticabnormalities
is associatedwiththe development
of this disease?
A. expandedtrinucleotide
repeat
B. extra X chromosome
C. frameshiftmutation+
D. genomicimprinting
gene mutation
E. mitochondrial
F. nondisjunction
Laboratory
studiesof this patientdemonstrate
decreasedactivityof hexosaminidase
A. Whichof the
followingis the correctdiagnosis?
A. Gaucherdisease
B. McArdledisease
C. Niemann-Pick
disease,type I B
D. Pompedisease
E. Tay-Sachsdisease CF. von Gierkedisease
lf the parentsof the childdescribedabovehavea totalof four sonsand two daughters,
then,on average,
how manyof theirchildrenmay be expectedto be silentcarriersof this genemutation?
A. one child
'

B. two children
C. threechildren ,CD. four children
E. five children

2013 GeneticDisordersReview- Part 1; BarbaraD. Bosch,M.D. page 10

Tay-Sachsdisease(autosomalrecessive)
. lysosomalstoragedisorder;morefrequentin AshkenaziJews
.

mutationsat the o-subunitlocusof hexosaminidase

A + I'd hexosaminidase
A activitv+
accumulation
of GM2gangliosides

characterized
by distended,vacuolatedneurons(witheventualneuronaldegeneration)
throughoutthe brain,spinalcord,autonomicnervoussystem,and retina

infantileform is the mostcommon,with symptomsbeginningby 6 monthsof age;typical

presentation
is the progressive
lossof motorskills,cognitiveabilitiesand vision(macular

+ deathusuallyby 2-3 yearsof age

), as wellas hyperacusis
diagnosedby enzymeassaysand DNAanalysis

A 37 year-oldwomangivesbirthat 35 weeks'gestation
to a femaleinfantwho is observedto have
multipleabnormalities,
includinga smalllowerjaw, low-setears,rocker-bottom
feet,and handsthat are
clenchedintofists. Despitesupportive
therapyfor a congenitalheartcondition,the babydies before1
yearof age. What is the likelyetiologyof the patient'scondition?
A. deletionof band 11 on chromosome
22
B. deletionof chromosome
21
C. maternalimprinting
D. trisomyof chromosome13
uf pt -kt'<L
E. trisomyof chromosome16 ' rqcelca**ro\ q].i.nJ4
F. trisomyof chromosome18 ?

stsca't'"-Zz

2013 GeneticDisordersReview- Part 1; BarbaraD. Bosch,l\4.D. page 'l 1

Edwardssyndrome (trisomy 18i 47,XX,+18or47,XY,+18)

o riskincreaseswith maternalage
o

usuallycausedby meioticnondisjunction
clinicalfindingsincludementalretardation,
microcephaly
witha prominentocciput,low-setears,
micrognathia,
clenchedhandswithoverlapping
fingers,and rocker-bottom
feet
commonlyassociated
withcongenitalheartdefects,as well as renaland Gl abnormalities
very poorprognosisdue to severemalformations

A 20 year-oldwomanknownto havean inbornerrorof metabolism

is planningfor herfirstpregnancy.
She is advisedby her physicianto begina phenylalanine-free
dietbeforeconceptionand to continuethis
dietthroughoutall threetrimestersof her pregnancy.Thisspecialdietis mostlikelyto aid in preventing
whichof the followingproblemsin her infant?
A. anemia
B. cataracts
C. congestiveheartfailure
D. mentalretardation (E. muscularweakness
Phenylketonuria
is an autosomalrecessivediseasethat causesseverementalretardation
if it is
undeiected.Two normalparentsare told by theirsiate neonatalscreeningprogramthat theirthirdchild
has PKU. Assumingthat thisscreeningis accurate,what is the riskthattheirfirstchild(whoappearsto
be unaffected)is a carrierfor PKU?
A. 100%
B. 670/0?
C.5oo/o
D. 25o/o
E. virtually0%

2013 GeneticDisordersReview- Part 1; Barba D. Bosch,N4.D. page'12

Phenylketonuria(autosomalrecessive)
. mostcommonlycausedby a deficiencyof phenylalanine
hydroxylase,
resultingin toxiclevelsof
phenylalanine
infantis normalat birth,but developsprofoundmentalretardation
by 6 monthsof age without
dietaryrestriction
of phenylalanine
lackof tyrosineleadsto fair hairand skin
may be associatedwitha mousyor mustvodorto the sweatand urine(dueto the productionof
abnormalmetabolites
in minorshuntpathways)
diagnosedby routinenewbornscreening
a

mildervariantscharacterized
by lesserdegreesof enzymedeficiencywithonlyslightlyelevated
phenylalanine
(benign
levelsthat are insufficlent
to causementalretardation
hyperphenylalaninemia)

An 8 month-oldmaleinfantis broughtto the pediatrician

by his parentsbecausehe has recentlylostthe
abilityto crawlor holdhis toys. His mothersaysshe took himto the emergencydepartmentlastweek
becausehe was wheezing.He was diagnosedwith a cold and givenan antihistamine,
whichdid not
relievehis symptoms.On examination,
the patientis tachypneicand breathingwithconsiderable
effort;
the liveris palpablefivefingerwidths
belowtherightcostalmargin.X-rayfilm of the chestreveals
cardiomegaly.He has a difficulttime sittinguprightand cannotsqueezethe physician's
fingersor the
ringof his pacifierwith any noticeable
force. Despitea numberof interventions,
the child'ssymptoms
continueto worsenuntilhis deathtwo weekslater. The microscopic
appearance
of his myocardium
at
photomicrograph.
autopsyis shownin the accompanying
Whichof the followingsubstanceshas most
likelyaccumulated
withinthesecells?
A. glucocerebroside
B. glucose
C. glycogen*D. cM2 ganglioside
E. heparansulfate
F. sphingomyelin
Whichof the followingenzymesis deficientin this condition?
A. acid maltase *
B. glycogenbranchingenzyme
C. glycogendebranching
enzyme
D. musclephosphofructokinase
E. myophosphorylase

2013GeneticDisorders
Review-Pad 1;BarbaraD. Bosch,l\4.D. page13

Pompe disease(autosomalrecessive)
.

type ll glycogenstoragediseasecharacterized
by a deficiencyof lysosomalacido-glucosidase
(acid
maltase),requiredfor the degradation
of a smallpercentage
of cellularglycogen

infantileformis the mostcommon,characterized

by cardiomegaly,
hepatomegaly,
hypotonia,and
weakness(dueto the accumulation
of glycogen);usuallydeathfrom heartfailureby the age of 2

diagnosisestablished
by enzymeanalysis

Bonus question:
Mr. Smithis affectedwith Crouzonsyndromeand has craniosynostosis
(premature
closureof the skull
sutures),alongwith an unusualfacialappearance
that includesproptosissecondaryto shalloworbits,
hypoplasia
of the maxillaand a prominentnose. His son and brotherare alsoaffected,althoughtwo
daughtersand his wife are not. Mr. and Mrs.Smithare considering
havinganotherchild. Thelr
physiciancounselsthemthatthe riskthatthe childwill be affectedwith Crouzonsvndromeis whichof
the following?
A. '100%
B. 670/0

C. 50Yo 4D. 25%

E. virtuallv0%